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A Proteomic Network Approach Across the ALS-FTD Disease Spectrum

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A Proteomic Network Approach Across the ALS-FTD Disease Spectrum A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain Mfon E Umoh, Emory University School of Medicine Eric Dammer, Emory University Jingting Dai, Emory University School of Medicine Duc M Duong, Emory University School of Medicine James Lah, Emory University Allan Levey, Emory University Marla Gearing, Emory University Jonathan Glass, Emory University Nicholas Seyfried, Emory University Journal Title: EMBO Molecular Medicine Publisher: Wiley Open Access | 2017-01-01 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.15252/emmm.201708202 Permanent URL: https://pid.emory.edu/ark:/25593/s730k Final published version: http://dx.doi.org/10.15252/emmm.201708202 Copyright information: © 2017 EMBO. This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Accessed September 30, 2021 4:20 AM EDT Research Article A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain Mfon E Umoh1,2,†, Eric B Dammer2,3,†, Jingting Dai2,3, Duc M Duong2,3, James J Lah1,2, Allan I Levey1,2, Marla Gearing1,2,4, Jonathan D Glass1,2,4,* & Nicholas T Seyfried1,2,3,** Abstract Subject Categories Neuroscience; Post-translational Modifications, Proteoly- sis & Proteomics Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia DOI 10.15252/emmm.201708202 | Received 27 June 2017 | Revised 13 October (FTD) are neurodegenerative diseases with overlap in clinical 2017 | Accepted 20 October 2017 | Published online 30 November 2017 presentation, neuropathology, and genetic underpinnings. The EMBO Mol Med (2018) 10: 48–62 molecular basis for the overlap of these disorders is not well estab- lished. We performed a comparative unbiased mass spectrometry- based proteomic analysis of frontal cortical tissues from post- Introduction mortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia C9orf72 expansion mutation, the most common genetic cause of (FTD) are clinically distinct neurodegenerative diseases that are both ALS and FTD. Our systems-level analysis of the brain connected by genetic and pathological overlap (Fecto & Siddique, proteome integrated both differential expression and co-expres- 2011; Ferrari et al, 2011; Achi & Rudnicki, 2012). ALS patients sion approaches to assess the relationship of these differences to present with muscle weakness and spasticity associated with clinical and pathological phenotypes. Weighted co-expression degeneration of motor neurons in the motor cortex, brainstem, network analysis revealed 15 modules of co-expressed proteins, and spinal cord that ultimately leads to death. In contrast, eight of which were significantly different across the ALS-FTD patients with FTD display cognitive dysfunction associated with disease spectrum. These included modules associated with RNA degeneration of neurons in the frontal and temporal lobes of the binding proteins, synaptic transmission, and inflammation with brain. Despite being clinically distinct, 15% of individuals cell-type specificity that showed correlation with TDP-43 pathol- presenting with FTD also have ALS, whereas 30% of individuals ogy and cognitive dysfunction. Modules were also examined for with ALS will develop FTD (Lomen-Hoerth, 2011). This implies their overlap with TDP-43 protein–protein interactions, revealing that these two neurodegenerative diseases are part of a shared one module enriched with RNA-binding proteins and other causal clinical spectrum. ALS genes that increased in FTD/ALS and FTD cases. A module In addition to their clinical overlap, most cases of ALS and enriched with astrocyte and microglia proteins was significantly FTD display pathological accumulation of TAR-DNA binding increased in ALS cases carrying the C9orf72 mutation compared to protein (TDP-43), a ubiquitously expressed nuclear DNA/RNA sporadic ALS cases, suggesting that the genetic expansion is asso- binding protein that is cleaved, phosphorylated, and aggregated in ciated with inflammation in the brain even without clinical the cytoplasm in disease (Neumann et al, 2006). Ninety-seven evidence of dementia. Together, these findings highlight the utility percent of ALS cases display phosphorylated TDP-43 pathology in of integrative systems-level proteomic approaches to resolve clini- the brain and/or spinal cord, while 50% of FTD cases display cal phenotypes and genetic mechanisms underlying the ALS-FTD this pathology throughout the brain (Radford et al, 2015), defin- disease spectrum in human brain. ing these diseases as TDP proteinopathies. Many individuals with ALS and FTD also share a positive family history of disease (Fong Keywords C9orf72 expansion mutation; mass spectrometry; neurodegenera- et al, 2012). The largest proportion of inherited cases (40% ALS tion; protein co-expression; TDP-43 and 25% FTD) are caused by hexanucleotide G4C2 repeat 1 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA 2 Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA 3 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA 4 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA *Corresponding author. Tel: +1 404 727 3275; E-mail: [email protected] **Corresponding author. Tel: +1 404 712 9783; E-mail: [email protected] †These authors contributed equally to this work 48 EMBO Molecular Medicine Vol 10 |No1 | 2018 ª 2017 The Authors. Published under the terms of the CC BY 4.0 license Mfon E Umoh et al ALS-FTD proteomic network EMBO Molecular Medicine expansions in the C9orf72 gene, which notably were identified Results from families with co-occurring ALS and FTD (ALS/FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011; Majounie Proteomic signature of human brain classifies cases by et al, 2012; Radford et al, 2015). Although the function of the clinical phenotypes C9orf72 protein is not yet known, there are several theories regarding how the C9orf72 mutation leads to ALS and FTD This study offers an in-depth analysis of protein changes in the (Zhang et al, 2012; Farg et al, 2014). For example, loss of frontal cortex of patients across the ALS-FTD disease spectrum, C9orf72 protein expression is thought to inhibit autophagy and which resulted in the final quantification of 2,612 protein groups promote neuroinflammation (Farg et al, 2014; Webster et al, mapping to 2,536 unique gene symbols across all samples (Datasets 2016), whereas expression of C9orf72 gene products could cause EV1 and EV2). Our goal was to compare ALS patients with and toxicity via nuclear sense and antisense repeat-containing RNAs without clinical dementia, so our experimental case selection that sequester RNA binding proteins (abnormal RNA metabolism) grouped samples based on clinical phenotype. As FTD is clinically or by non-canonical repeat-associated non-ATG (RAN) translation heterogeneous, we limited that group to include only individuals of dipeptide repeat proteins that aggregate and block nuclear with the pathological diagnosis of frontotemporal lobar degenera- pores (Gitler & Tsuiji, 2016). Notably, this genetic mutation tion with TDP-43 inclusions (FTLD-TDP), which accounts for the bridges these two diseases that clinical and pathological overlaps majority of overlap with ALS and FTD (Neumann et al, 2009). The have previously connected. However, the underlying molecular frontal cortex was chosen because it was a likely site for discrimi- basis of the ALS-FTD clinical and pathological spectrum is not nating proteomic differences in ALS patients with and without well established. It is also unclear why patients with the same dementia, and represents an area in which TDP-43 pathological C9orf72 genetic expansion get either or both of these disparate burden has been mapped in FTD patients (Brettschneider et al, diseases. Using our knowledge of the shared clinical, pathological, 2014). In our analytic pipeline, protein expression values are and genetic features characterizing ALS and FTD, a systems-level adjusted for age, sex, and postmortem interval (PMI) covariance proteomic analysis of both sporadic and genetic (C9orf72) cases prior to downstream differential or co-expression analyses comprising the ALS-FTD spectrum was conducted to determine (Fig EV1). Differential expression by ANOVA comparisons of each common and distinct pathways that contribute to the onset and of the groups yielded subsets of significantly altered proteins across development of dementia. controls and disease groups (Dataset EV2). The number of signifi- Co-expression network analysis has been used to define modules cantly altered proteins increased sequentially when comparing of co-expressed genes or proteins linked to specific cell types, orga- controls to ALS, ALS-FTD, and FTD, respectively, which is likely nelles, and biological pathways (Miller et al, 2008; Oldham, 2014; due to the presence of clinical dementia and an increase in associ- Seyfried et al, 2017). Assessing co-expression of proteins within ated pathological burden in the frontal cortex (Fig 1A). For super- samples and relating co-expression modules to clinical and patho- vised clustering analysis, we selected 165 proteins that had at least
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